Cheng Yong, Zheng Wei, Dong Xinru, Sun Tengxiao, Xu Mengwei, Xiang Li, Li Jian, Wang Huilong, Jian Xiaoqin, Yu Jingjin, Li Pengcheng, Hu Tianwen, Tian Guanghui, Jiang Xiangrui, Zhang Leike, Aisa Haji A, Xie Yuanchao, Xiao Gengfu, Shen Jingshan
State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences; Urumqi 830011, P. R. China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences; Shanghai 201203, P. R. China.
J Med Chem. 2025 May 8;68(9):9811-9826. doi: 10.1021/acs.jmedchem.5c00626. Epub 2025 Apr 28.
4'-Fluorouridine (4'-FU), despite demonstrating potent anti-SFTSV efficacy in vitro and in vivo, faces hindrances in its further development as a promising drug due to its weak chemical stability. Here, we report the discovery and development of VV261, a novel 4'-FU double prodrug with three isobutyryl groups on the ribose moiety and a nicotinoyloxymethyl group linked to the imide-nitrogen on the base moiety, exhibiting notable chemical stability and favorable pharmacokinetic properties. In SFTSV-infected mice, VV261 at 5 mg/kg/d for 7 days demonstrated complete protection against lethal SFTSV infection, prevented weight loss, and even a 2 day treatment significantly reduced both viral RNA copies and infectious virus titers in multiple organs, and notably alleviated splenic tissue lesions. After further preclinical evaluations, VV261, identified as a promising candidate drug for the treatment of SFTS, has entered Phase I clinical trials in China, the first such candidate to reach this stage for SFTS.
4'-氟尿苷（4'-FU）尽管在体外和体内均显示出强大的抗严重发热伴血小板减少综合征病毒（SFTSV）功效，但由于其化学稳定性较弱，在作为一种有前景的药物进一步开发过程中面临阻碍。在此，我们报告了VV261的发现与开发，这是一种新型的4'-FU双前药，在核糖部分有三个异丁酰基，在碱基部分的酰亚胺氮上连接有一个烟酰氧基甲基，具有显著的化学稳定性和良好的药代动力学性质。在感染SFTSV的小鼠中，以5毫克/千克/天的剂量给予VV261，持续7天，可对致死性SFTSV感染提供完全保护，防止体重减轻，甚至进行为期2天的治疗也能显著降低多个器官中的病毒RNA拷贝数和感染性病毒滴度，并显著减轻脾脏组织病变。经过进一步的临床前评估后，VV261被确定为治疗SFTS的一种有前景的候选药物，已在中国进入I期临床试验，它是首个进入该阶段的用于治疗SFTS的此类候选药物。
